mica00_metastasis.jpg

A new class of vaccine stops metastatic cancer from escaping the immune system

mica00_metastasis.jpg

A metastasized lymph node in a person with non-small cell lung cancer

Metastatic cancer is a toughie, but it’s a common aftermath of surgery on aggressive tumors. Things may be fine for a while, but then the cancer often reestablishes itself in multiple locations because bits of that original tumor somehow got loose and colonized other parts of the body.

The immune system will certainly attack cancer cells, but metastatic cancer can simply overwhelm it. So one way to go after this problem is to prep the immune system to make things more manageable. How do we do that? With a vaccine, of course!

For a terrific mini-review of the cancer-vaccine topic, with all the potential treatments in the works, I’d point you to an article by Jocelyn Kaiser of Science from about a month and a half ago. She zooms out from an individual case to the very big picture, including the prospect of a generic cancer vaccine — sort of a War And Peace vibe — in like 5 pages. Superbly written.

I won’t try to do that here, but rather we’ll look at a brand-new class of treatments of this sort in a teeny bit more detail, to give you an idea of ​​the thought process and the tools that go into fighting cancer today. Dr. Kai Wucherpfennig of Harvard, Dana-Farber, and Brigham and Women’s and his associates describe it in the May 25 issue of Nature. (I thank Dr. W for kindly sending me a reprint so I don’t have to subscribe to expensive journals!)

You know, cancer cells really are little bastards in many ways. One of the rottenest things they do is undermine a natural feature of the immune system that’s designed to go after malfunctioning cells. When something is irreversibly wrong with a normal cell, it gives itself up by hoisting a “come get me” flag for the immune system. Cells have a protein called MICA (and another nearly identical one called MICB) that they will display out on their surfaces at high levels if they become infected, have DNA damage, or are mega-stressed in other ways (like turning into a cancer cell ). natural killer (NK) cells can spot this flag with a detector called NKG2D and alert the immune system (other NK cells and T cells) that the situation needs to be dealt with.

But cancer cells often eventually figure out how to snip MICA off their surfaces, sending it all over the place in the body and thus disorienting the immune system. You don’t see any free MICA floating around in the sera of healthy patients, but you do often see high levels of it in patients with malignant tumors or even precancerous growths, because the cancer cells displayed it as a stress tag, like they were supposed to, but then cut it off.

Not only does free MICA confuse the immune system, but any NK cell that grabs onto a free-floating MICA becomes weakened and also somehow stimulates immunosuppressive T cells, which tamp down the overall immune response and leave you more susceptible to infections generally. So this snipping of MICA by cancer cells screws you over in two ways.

Here’s a good pictorial recap of this:

mica03_detach.jpg
Left: normal immunosurveillance by NK cells. Right: sabotage of this feature by MICA-snipping.

So now the question is, can we make cancer cells stop clipping MICA off their surfaces?

Wucherpfennig and colleagues got the idea that they could develop a vaccine to prevent this snipping nonsense so that the immune system can still spot MICA on the surfaces of cancer cells and thus be able to polish off any metastatic remnants.

Let’s look a little more closely at the structure of MICA, because its three little domains are very important here. Notice that the α1 and α2 domains are the ones that hook up with NKG2D, while the α3 domain isn’t involved in that:

mica04_domains.jpg
The basic structure of MICA as it relates to NKG2D binding

But the thing is, the MICA-snipping action does take place at α3, so what we need is an antibody to bind only to α3 and cover it up. Then we could stop this snipping yet still allow NK cells to dock with MICA at α1 and α2 like they should. A vaccine containing only the α3 part of MICA will induce exactly the antibodies we want.

A good way to crank up the immune response to a vaccine is to make sure the protein contained in the vaccine is as obvious as possible. One recently developed and very nifty way to do that is to attach our α3 protein to another protein called ferritin. If you’ve ever been anemic, you were probably tested for your ferritin level, because its job is to store iron.

What makes ferritin so useful here is that 24 ferritin molecules get together to form a spherical cage within which iron particles are kept. This is what one of those cages typically looks like:

mica01_ferritin.gif
An empty ferritin cage

You can imagine that if an α3 is stuck to each ferritin molecule on that sphere, it’s going to be pointed in every direction, so the immune system has got to notice that. This is the same sort of strategy coronavirus employees; with spike proteins distributed all over its spherical surface, it won’t be long before one of them bumps into the right cell receptor.

Ferritin’s day job is a little different, though. It converts water-soluble iron(II) into not-so-soluble iron(III) and stores it as a ferrihydrite mineral — some variety of FeO(OH) — at the center of the cage. And that’s a good thing, because if iron(II) ions are allowed to float around freely in the body, they can catalyze the breakup of hydrogen peroxide (H2O2) into free radicals via the Fenton reactionand then those can go on to damage DNA, proteins, and just about any other cellular component in their path:

2 hours2O2 → HO + HOO +H2O

Instead, thanks to ferritin, the iron is safely tucked away in a mineral form not unlike rust:

mica02_ferrihydrite.jpg
Synthetic ferrihydrite

But I digress. (Don’t I always?)

Anyway, now we inject our ferritin-α3 balls as the vaccine just after tumor excision. The immune system will make antibodies to α3, to cover up the MICA-snipping spot. And it’ll keep on attacking MICA stuck to cancer cells, which it was doing already. But now the crafty little cancer cells can’t escape NK cells by snipping MICA off their surfaces, and as a result they are now in a bit more trouble.

The first series of tests was on mice with induced aggressive melanoma tumors. These mice were genetically engineered to express human MICB protein, which mouse NKG2D is known to bind well. The human MICB was shed by mouse tumors, just as in human cancers. Two days after the main tumor was removed, the vaccine was given, then a booster was given ten days after that. A strong antibody response was seen, and those antibodies clung to MICB-expressing tumors but not control tumors. Then in four weeks metastatic tumors on the lungs were examined:

mica05_mouse.jpg
“Ctrl-Vax” = ferritin only, “MICB-vax” = ferritin plus the α3 portion of MICB

You can see that after the MICB vaccine is given, the metastases just can’t seem to get going because they are being actively attacked by the mouse’s immune system. The authors showed that NK cells and also T cells were attacking the metastases. Sera from these mice were also shown to stop MICA and MICB shedding from human cancer cell lines.

The vaccine was tested in rhesus macaques (this time targeting the monkeys’ own MICA and MICB proteins), who did a great job producing anti-MICA/MICB antibodies. After the booster, the response went up 100 to 1000 times, with no clinical side effects.

Our next step, of course, is trials in human cancer patients, especially those showing higher levels of MICA shedding. Let’s get it on.

This kind of vaccine takes advantage of knowledge about MICA that we’ve only had for a decade or so and clearly illustrates that there is still a lot more fertile ground to cover in our fight against cancer. There won’t be a single silver bullet because cancer is really many diseases. But one by one, its secrets are being exposed. If it keeps on raining….

Leave a Comment

Your email address will not be published. Required fields are marked *